JP2019038746A - 4-phenyl-4-oxobutanoic acid derivative - Google Patents

Abstract

To provide a compound useful as an agent for treating/or preventing a disease caused by an abnormality in a mitochondrial function.SOLUTION: The present invention provides a 4-phenyl 4-oxobutanoic acid derivative illustrated by formula III-3 and a pharmaceutically acceptable salt thereof. The present invention provides a therapeutic agent that is applied to a disease caused by a mitochondrial function disorder, which is mitochondrial disease, neurodegenerative disease, immunologic neurological disease, brain ischemic disease, renal disease, myopathy, or cardiac disease.SELECTED DRAWING: None

Description

  The present invention relates to a 4-phenyl-4-oxobutanoic acid derivative useful as a medicine, or a pharmaceutically acceptable salt thereof. More particularly, the present invention relates to a pharmaceutical composition containing a 4-phenyl-4-oxobutanoic acid derivative or a pharmaceutically acceptable salt thereof. The present invention relates to a therapeutic / prophylactic agent containing a novel 4-phenyl-4-oxobutanoic acid derivative containing the compound or a pharmaceutically acceptable salt thereof.

  Mitochondria are the main energy supply organs in cells, and are present in many tissues (for example, brain, skeletal muscle, heart muscle, kidney, etc.) that are actively active and have high energy requirements in human body tissues.

  Decreased mitochondrial function associated with genetic background and aging causes various diseases. A typical example is known as a disease generally called mitochondrial disease. An effective treatment for a patient suffering from mitochondrial disease has not yet been found, only symptomatic treatment is given to some symptoms, and treatment satisfaction is not high. Accordingly, there is a need for new drugs that improve mitochondrial dysfunction and thereby exert efficacy.

In addition, mitochondrial dysfunction inhibits the activities of energy-requiring tissues, and thus may cause various diseases other than mitochondrial diseases (for example, neurodegenerative diseases, muscle diseases, heart diseases, kidney diseases, etc.). There are many diseases that are known and among which there is not enough treatment.
For example, amyotrophic lateral sclerosis (ALS) is a disease with a poor prognosis in which the cause of its onset is still unknown and causes significant muscle atrophy as a symptom, resulting in movement disorders, difficulty swallowing, and respiratory failure. For example, riluzole is known as an ALS therapeutic agent, but it only shows the effect of delaying the progression of symptoms for several months. In addition, there are currently no effective treatments for diseases such as Parkinson's disease, Alzheimer's disease, muscular dystrophy, sarcopenia, and disuse muscle atrophy.

  Patent Document 1 discloses indoleacetic acid derivatives and the like useful as therapeutic agents for mitochondrial diseases and the like.

International Publication No. 2014/080640

  An object of the present invention is to provide a novel compound useful as a therapeutic / prophylactic agent for diseases associated with abnormal mitochondrial function.

  The present inventors have found that a compound represented by the following formula (1) and a pharmaceutically acceptable salt thereof (hereinafter sometimes abbreviated as “the compound of the present invention” as necessary) have an effect of improving mitochondrial function. As a result of diligent research to solve the above-mentioned problems, the compound of the present invention is a cell that is prominent against cell death induced by oxidative stress load in patient cells with diseases involving mitochondrial dysfunction It has been found that it exhibits a death-inhibiting action, and the present invention has been completed.

That is, the present invention is as follows.
[1] The following formula (I):

［式中、Ｘ^ａ、Ｘ^ｂ、Ｘ^ｃおよびＸ^ｄは、各々独立して、水素原子、フッ素原子、塩素原子、Ｃ_１−４アルキル基、またはＣ_１−４アルコキシ基を表し；
Ａは、
（ａ）下記式（II）：

[Wherein, X ^a , X ^b , X ^c and X ^d each independently represent a hydrogen atom, a fluorine atom, a chlorine atom, a C _1-4 alkyl group, or a C _1-4 alkoxy group;
A is
(A) The following formula (II):

（式中、
（１）Ｙ^ａ、Ｙ^ｂ、Ｙ^ｃ、Ｙ^ｄおよびＹ^ｅのうち、１〜３個が各々独立して、塩素原子を表し、残りは、各々独立して、水素原子、フッ素原子、Ｃ_１−４アルキル基、またはＣ_１−４アルコキシ基を表すか；
（２）Ｙ^ａ、Ｙ^ｂ、Ｙ^ｃ、Ｙ^ｄおよびＹ^ｅのうち、１〜３個が各々独立してＣ_１−４アルキル基を表し、残りは、各々独立して、水素原子、フッ素原子、またはＣ_１−４アルコキシ基を表すか；
（３）Ｙ^ａ、Ｙ^ｂ、Ｙ^ｃ、Ｙ^ｄおよびＹ^ｅのうち、１〜３個が各々独立して、Ｃ_１−４アルコキシ基を表し、残りは、各々独立して、水素原子、またはフッ素原子を表す）で表される基、または
（ｂ）１〜５個のフッ素原子で置換されているＣ_４−６アルキル基を表すが、
以下の化合物：
４−（４−クロロフェニル）−２−（１Ｈ−インドール−３−イル）−４−オキソブタノイック アシッド、
６，６，７，７，７−ペンタフルオロ−２−（１Ｈ−インドール−３−イル）ヘプタノイック アシッド、
４−（３，４−ジクロロフェニル）−２−（１Ｈ−インドール−３−イル）−４−オキソブタノイック アシッド、
４−（４−クロロ−３−メチルフェニル）−２−（１Ｈ−インドール−３−イル）−４−オキソブタノイック アシッド、
２−（１Ｈ−インドール−３−イル）−４−（４−メチルフェニル）−４−オキソブタノイック アシッド、
２−（１Ｈ−インドール−３−イル）−４−オキソ−４−（４−プロピルフェニル）ブタノイック アシッド、
２−（１Ｈ−インドール−３−イル）−４−オキソ−４−［（４−プロパン−２−イル）フェニル］ブタノイック アシッド、
４−（４−ｔｅｒｔ−ブチルフェニル）−２−（１Ｈ−インドール−３−イル）−４−オキソブタノイック アシッド、
４−（２，４−ジメチルフェニル）−２−（１Ｈ−インドール−３−イル）−４−オキソブタノイック アシッド、
４−（３，４−ジメチルフェニル）−２−（１Ｈ−インドール−３−イル）−４−オキソブタノイック アシッド、
４−（２，５−ジメチルフェニル）−２−（１Ｈ−インドール−３−イル）−４−オキソブタノイック アシッド、
２−（１Ｈ−インドール−３−イル）−４−（４−メトキシフェニル）−４−オキソブタノイック アシッド、
４−（４−エトキシフェニル）−２−（１Ｈ−インドール−３−イル）−４−オキソブタノイック アシッド、
４−（４−ｔｅｒｔ−ブチルフェニル）−２−（７−エチル−１Ｈ−インドール−３−イル）−４−オキソブタノイック アシッド、
４−（４−エトキシフェニル）−２−（６−メトキシ−１Ｈ−インドール−３−イル）−４−オキソブタノイック アシッド、
を除く]で表される化合物またはその製薬学的に許容される塩。

(Where
(1) 1 to 3 of Y ^a , Y ^b , Y ^c , Y ^d and Y ^e each independently represent a chlorine atom, and the rest each independently represents a hydrogen atom, a fluorine atom, C Represents a _1-4 alkyl group or a C _1-4 alkoxy group;
(2) Among Y ^a , Y ^b , Y ^c , Y ^d and Y ^e , 1 to 3 each independently represents a C _1-4 alkyl group, and the rest each independently represents a hydrogen atom, fluorine Represents an atom or a C _1-4 alkoxy group;
(3) 1-3 of Y ^a , Y ^b , Y ^c , Y ^d and Y ^e each independently represent a C _1-4 alkoxy group, and the rest each independently represents a hydrogen atom, Represents a fluorine atom, or (b) a C _4-6 alkyl group substituted with 1 to 5 fluorine atoms,
The following compounds:
4- (4-chlorophenyl) -2- (1H-indol-3-yl) -4-oxobutanoic acid,
6,6,7,7,7-pentafluoro-2- (1H-indol-3-yl) heptanoic acid,
4- (3,4-dichlorophenyl) -2- (1H-indol-3-yl) -4-oxobutanoic acid,
4- (4-chloro-3-methylphenyl) -2- (1H-indol-3-yl) -4-oxobutanoic acid,
2- (1H-indol-3-yl) -4- (4-methylphenyl) -4-oxobutanoic acid,
2- (1H-indol-3-yl) -4-oxo-4- (4-propylphenyl) butanoic acid,
2- (1H-indol-3-yl) -4-oxo-4-[(4-propan-2-yl) phenyl] butanoic acid,
4- (4-tert-butylphenyl) -2- (1H-indol-3-yl) -4-oxobutanoic acid,
4- (2,4-dimethylphenyl) -2- (1H-indol-3-yl) -4-oxobutanoic acid,
4- (3,4-dimethylphenyl) -2- (1H-indol-3-yl) -4-oxobutanoic acid,
4- (2,5-dimethylphenyl) -2- (1H-indol-3-yl) -4-oxobutanoic acid,
2- (1H-indol-3-yl) -4- (4-methoxyphenyl) -4-oxobutanoic acid,
4- (4-ethoxyphenyl) -2- (1H-indol-3-yl) -4-oxobutanoic acid,
4- (4-tert-butylphenyl) -2- (7-ethyl-1H-indol-3-yl) -4-oxobutanoic acid,
4- (4-ethoxyphenyl) -2- (6-methoxy-1H-indol-3-yl) -4-oxobutanoic acid,
Or a pharmaceutically acceptable salt thereof.

[2] The compound according to [1] or a pharmaceutically acceptable salt thereof, wherein A is a group represented by the formula (II).

[3] 1-3 of Y ^a , Y ^b , Y ^c , Y ^d and Y ^e are each independently a chlorine atom; the rest are each independently a hydrogen atom, a fluorine atom, C ₁ Or a pharmaceutically acceptable salt thereof according to [1] or [2], which is a _-4 alkyl group or a _C1-4 alkoxy group.

[4] Among Y ^a , Y ^b , Y ^c , Y ^d and Y ^e , 1 to 3 are each independently a chlorine atom; the rest are each independently a hydrogen atom, a fluorine atom, or C The compound or a pharmaceutically acceptable salt thereof according to [1] or [2], which is a _1-4 alkyl group.

[5] Among Y ^a , Y ^b , Y ^c , Y ^d and Y ^e , 1 to 3 are each independently a C _1-4 alkyl group; the rest are each independently a hydrogen atom, fluorine The compound or a pharmaceutically acceptable salt thereof according to [1] or [2], which is an atom or a C _1-4 alkoxy group.

[6] Of Y ^a , Y ^b , Y ^c , Y ^d and Y ^e , 1 to 3 are each independently a C _1-4 alkyl group; the rest are each independently a hydrogen atom or The compound or a pharmaceutically acceptable salt thereof according to [1] or [2], which is a fluorine atom.

[7] The compound or a pharmaceutically acceptable salt thereof according to any one of [1] to [6], wherein Y ^c is a chlorine atom or a C _1-4 alkyl group.

[8] 1-3 of Y ^a , Y ^b , Y ^c , Y ^d and Y ^e are each independently a C _1-4 alkoxy group; the rest are each independently a hydrogen atom or fluorine. The compound or a pharmaceutically acceptable salt thereof according to [1] or [2], which is an atom.

[9] The compound according to [1] or a pharmaceutically acceptable salt thereof, wherein A is a C _4-6 alkyl group substituted with 1 to 5 fluorine atoms.

[10] At least one of X ^a , X ^b , X ^c and X ^d is a fluorine atom, a chlorine atom, a C _1-4 alkyl group or a C _1-4 alkoxy group, [1] to [9] Or a pharmaceutically acceptable salt thereof.

[11] The compound according to [1] or a pharmaceutically acceptable salt thereof selected from the following compounds:
4- (2,4-dichlorophenyl) -2- (1H-indol-3-yl) -4-oxobutanoic acid (Example 1),
4- (3-chlorophenyl) -2- (1H-indol-3-yl) -4-oxobutanoic acid (Example 6),
4- (2,4-dichlorophenyl) -2- (5-fluoro-1H-indol-3-yl) -4-oxobutanoic acid (Example 7),
4- (2,4-dichlorophenyl) -2- (6-fluoro-1H-indol-3-yl) -4-oxobutanoic acid (Example 8),
2- (5-Chloro-1H-indol-3-yl) -4- (2,4-dichlorophenyl) -4-oxobutanoic acid (Example 9),
2- (6-Chloro-1H-indol-3-yl) -4- (2,4-dichlorophenyl) -4-oxobutanoic acid (Example 10),
4- (2,4-dichlorophenyl) -2- (5-methyl-1H-indol-3-yl) -4-oxobutanoic acid (Example 11),
4- (2,4-dichlorophenyl) -2- (5-ethyl-1H-indol-3-yl) -4-oxobutanoic acid (Example 12),
4- (2,4-dichlorophenyl) -2- (5-methoxy-1H-indol-3-yl) -4-oxobutanoic acid (Example 13),
4- (2,4-dichlorophenyl) -2- (6-methoxy-1H-indol-3-yl) -4-oxobutanoic acid (Example 14),
4- (3-tert-butylphenyl) -2- (1H-indol-3-yl) -4-oxobutanoic acid (Example 19),
4- (4-tert-butylphenyl) -2- (5-fluoro-1H-indol-3-yl) -4-oxobutanoic acid (Example 21),
4- (4-tert-butylphenyl) -2- (5-chloro-1H-indol-3-yl) -4-oxobutanoic acid (Example 22),
4- (4-tert-butylphenyl) -2- (5-methyl-1H-indol-3-yl) -4-oxobutanoic acid (Example 24),
4- (4-tert-butylphenyl) -2- (5-methoxy-1H-indol-3-yl) -4-oxobutanoic acid (Example 27),
4- (4-tert-butylphenyl) -2- (6-methoxy-1H-indol-3-yl) -4-oxobutanoic acid (Example 28),
4- (2-chlorophenyl) -2- (1H-indol-3-yl) -4-oxobutanoic acid (Example 36),
8,8,8-Trifluoro-2- (1H-indol-3-yl) octanoic acid (Example 40).

[12] A compound selected from the following or a pharmaceutically acceptable salt thereof:
4- (3,4-difluorophenyl) -2- (1H-indol-3-yl) -4-oxobutanoic acid (Example 2),
4- (2,4-difluorophenyl) -2- (7-methyl-1H-indol-3-yl) -4-oxobutanoic acid (Example 3),
4- (2,4-difluorophenyl) -4-oxo-2- [6- (propan-2-yl) -1H-indol-3-yl] butanoic acid (Example 4),
4- (2,4-difluorophenyl) -2- (5-ethyl-1H-indol-3-yl) -4-oxobutanoic acid (Example 5),
2- (6-Chloro-1H-indol-3-yl) -4- (2,4-difluorophenyl) -4-oxobutanoic acid (Example 30),
4- (3,5-difluorophenyl) -2- (1H-indol-3-yl) -4-oxobutanoic acid (Example 31),
4- (2,4-difluorophenyl) -2- (4-methyl-1H-indol-3-yl) -4-oxobutanoic acid (Example 32),
4- (2,4-difluorophenyl) -2- (6-methyl-1H-indol-3-yl) -4-oxobutanoic acid (Example 33),
4- (2,4-difluorophenyl) -2- (7-ethyl-1H-indol-3-yl) -4-oxobutanoic acid (Example 34),
4- (2,4-difluorophenyl) -2- (4-methoxy-1H-indol-3-yl) -4-oxobutanoic acid (Example 35),
4- (2,5-difluorophenyl) -2- (1H-indol-3-yl) -4-oxobutanoic acid (Example 37),
4- (2,3-difluorophenyl) -2- (1H-indol-3-yl) -4-oxobutanoic acid (Example 38).

[13] A medicament comprising as an active ingredient the compound according to any one of [1] to [12] or a pharmaceutically acceptable salt thereof.

[14] A therapeutic agent for a disease caused by mitochondrial dysfunction, comprising as an active ingredient the compound according to any one of [1] to [12] or a pharmaceutically acceptable salt thereof.

[15] The following formula (I):

［式中、Ｘ^ａ、Ｘ^ｂ、Ｘ^ｃおよびＸ^ｄは、各々独立して、水素原子、フッ素原子、塩素原子、Ｃ_１−４アルキル基、またはＣ_１−４アルコキシ基を表し；
Ａは、
（ａ）下記式（II）：

[Wherein, X ^a , X ^b , X ^c and X ^d each independently represent a hydrogen atom, a fluorine atom, a chlorine atom, a C _1-4 alkyl group, or a C _1-4 alkoxy group;
A is
(A) The following formula (II):

（式中、
（１）Ｙ^ａ、Ｙ^ｂ、Ｙ^ｃ、Ｙ^ｄおよびＹ^ｅのうち、１〜３個が各々独立して、塩素原子を表し、残りは、各々独立して、水素原子、フッ素原子、Ｃ_１−４アルキル基、またはＣ_１−４アルコキシ基を表すか；
（２）Ｙ^ａ、Ｙ^ｂ、Ｙ^ｃ、Ｙ^ｄおよびＹ^ｅのうち、１〜３個が各々独立して、Ｃ_１−４アルキル基を表し、残りは、各々独立して、水素原子、フッ素原子、またはＣ_１−４アルコキシ基を表すか；
（３）Ｙ^ａ、Ｙ^ｂ、Ｙ^ｃ、Ｙ^ｄおよびＹ^ｅのうち、１〜３個が各々独立して、Ｃ_１−４アルコキシ基を表し、残りは、各々独立して、水素原子、またはフッ素原子を表す）で表される基、または
（ｂ）１〜５個のフッ素原子で置換されているＣ_４−６アルキル基を表すが、
４−（４−クロロフェニル）−２−（１Ｈ−インドール−３−イル）−４−オキソブタノイック アシッド、および６，６，７，７，７−ペンタフルオロ−２−（１Ｈ−インドール−３−イル）ヘプタノイック アシッドを除く] で表される化合物またはその製薬学的に許容される塩を有効成分として含有する、ミトコンドリア機能障害に起因する疾患の治療剤。

(Where
(1) 1 to 3 of Y ^a , Y ^b , Y ^c , Y ^d and Y ^e each independently represent a chlorine atom, and the rest each independently represents a hydrogen atom, a fluorine atom, C Represents a _1-4 alkyl group or a C _1-4 alkoxy group;
(2) 1-3 of Y ^a , Y ^b , Y ^c , Y ^d and Y ^e each independently represent a C _1-4 alkyl group, and the rest each independently represents a hydrogen atom, Represents a fluorine atom or a C _1-4 alkoxy group;
(3) 1-3 of Y ^a , Y ^b , Y ^c , Y ^d and Y ^e each independently represent a C _1-4 alkoxy group, and the rest each independently represents a hydrogen atom, Represents a fluorine atom, or (b) a C _4-6 alkyl group substituted with 1 to 5 fluorine atoms,
4- (4-Chlorophenyl) -2- (1H-indol-3-yl) -4-oxobutanoic acid and 6,6,7,7,7-pentafluoro-2- (1H-indole-3) A therapeutic agent for diseases caused by mitochondrial dysfunction, which comprises, as an active ingredient, a compound represented by -yl) excluding heptanoic acid or a pharmaceutically acceptable salt thereof.

[16] The disease according to [14] or [15], wherein the disease caused by mitochondrial dysfunction is mitochondrial disease, neurodegenerative disease, immune neurological disease, cerebral ischemic disease, renal disease, muscle disease, or heart disease Therapeutic agent.

[17] Mitochondrial diseases include Leigh's encephalopathy, stroke-like seizure syndrome (MELAS), chronic progressive extraocular palsy syndrome (CPEO), Kearns-Sayer syndrome (KSS), myoclonic epilepsy syndrome with red rag fibers (MERRF), The therapeutic agent according to [16], which is Pearson's disease, Leber hereditary optic neuropathy (LHON), mitochondrial encephalomyopathy, Bath syndrome, or lactic acidosis.

[18] The neurodegenerative disease is atrophic lateral sclerosis (ALS), Parkinson's disease, Alzheimer's disease, Huntington's disease, Friedreich ataxia, multiple system atrophy, progressive supranuclear palsy, spinocerebellar degeneration, [16] The therapeutic agent according to [16], which is spinal muscular atrophy, bulbar spinal muscular atrophy, or Charcot-Marie-Tooth disease.

[19] The therapeutic agent according to [16], wherein the immune neurological disorder is Guillain-Barre syndrome, multiple sclerosis, Fisher syndrome, chronic inflammatory demyelinating polyneuritis, or myasthenia gravis.

[20] The therapeutic agent according to [16], wherein the cerebral ischemic disease is cerebral infarction.

[21] Kidney disease is renal failure, amyloid kidney, membranous nephropathy, focal glomerulosclerosis, IgA nephropathy, acute tubular necrosis, nephrotic syndrome, diabetic nephropathy, gout kidney, renal edema, kidney The therapeutic agent according to [16], which is a tumor, renal ischemic injury, renal ischemia reperfusion injury, or cystic kidney.

[22] The muscle disease is progressive muscular dystrophy, myotonic dystrophy, congenital myopathy, metabolic myopathy, distal myopathy, inflammatory myopathy, age-related muscle atrophy (sarcopenia), or disuse muscle atrophy [16] The therapeutic agent according to [16].

[23] The therapeutic agent according to [16], wherein the heart disease is myocardial infarction, heart failure, ischemic heart disease, or cardiomyopathy.

  As another embodiment of the present invention, a method of treating a disease caused by mitochondrial dysfunction by administering the compound of the present invention to a patient in need of treatment of a disease caused by mitochondrial dysfunction, Production of the compound of the present invention for use as a therapeutic agent for diseases caused by dysfunction, the compound of the present invention for use in the treatment of diseases caused by mitochondrial dysfunction, and therapeutic agents for diseases caused by mitochondrial dysfunction The use of the compounds of the present invention to

  Since the compound of the present invention exhibits a remarkable cell death inhibitory action against cell death induced by oxidative stress in patient cells with diseases involving mitochondrial dysfunction, the therapeutic or preventive agent for diseases or symptoms involving mitochondrial dysfunction An agent can be provided. More specifically, it is useful as a therapeutic agent and / or preventive agent for mitochondrial diseases, or neurodegenerative diseases, immune neurological diseases, cerebral ischemic diseases, renal diseases, muscle diseases, and heart diseases.

The present invention is described in further detail below.
In the present specification, the number of substituents in the group defined as “may be substituted” or “substituted” is not particularly limited as long as substitution is possible, and is one or more.

In the present specification, the number of carbons in the definition of “substituent” may be expressed as “C _1-4 ”, for example. Specifically, the expression “C _1-4 alkyl” is synonymous with a linear or branched alkyl group having 1 to 4 carbon atoms.

  In this specification, the term “group” means a monovalent group. For example, “alkyl group” means a monovalent saturated hydrocarbon group. In addition, in the description of substituents in this specification, the term “group” may be omitted.

The “C _1-4 alkyl group” or “C _4-6 alkyl group” means a linear or branched saturated hydrocarbon group having 1 to 4 or 4 to 6 carbon atoms. Specific examples thereof include methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, sec-butyl group, tert-butyl group and the like in the case of “C _1-4 alkyl group”. Preferably, a methyl group, an ethyl group, a propyl group, and an isopropyl group are mentioned. In the case of “C _4-6 alkyl group”, in addition to the above, butyl group, isobutyl group, sec-butyl group, tert-butyl group, pentyl group, isopentyl group, neopentyl group, hexyl group and the like can be mentioned.

_{"C 1-4} alkoxy group" is synonymous with _{"C 1-4} alkyl group", the _{"C 1-4} alkyl group" moiety is the same as defined in the _{"C 1-4} alkyl group". Specific examples of the “C _1-4 alkoxy group” include, for example, a methoxy group, an ethoxy group, an n-propoxy group, an isopropoxy group, an n-butoxy group, an isobutoxy group, a sec-butoxy group, and a tert-butoxy group. It is done. Preferably, a methoxy group, an ethoxy group, n-propoxy group, or an isopropoxy group is mentioned.

_{"C 4-6} alkyl group" moiety of the "1-5 _{C 4-6} alkyl group substituted by a fluorine atom" is the same as defined in the _{"C 4-6} alkyl group". Specific examples of “C _4-6 alkyl group substituted with 1 to 5 fluorine atoms” include, for example, 4,4,4-trifluorobutyl group, 3,3,4,4,4-penta Fluorobutyl group, 5,5,5-trifluoropentyl group, 4,4,5,5,5-pentafluoropentyl group, 6,6,6-trifluorohexyl group, 5,5,6,6,6 -A pentafluorohexyl group etc. are mentioned. Preferably, 5,5,5-trifluoropentyl group, 4,4,5,5,5-pentafluoropentyl group, 6,6,6-trifluorohexyl group, or 5,5,6,6,6- A pentafluorohexyl group may be mentioned.

  The compounds of formula (I) may have one or more asymmetric carbon atoms and may cause geometric isomerism and axial chirality and therefore may exist as multiple stereoisomers. In the present invention, these stereoisomers, mixtures thereof and racemates are included in the compound represented by the formula (I) of the present invention.

The present invention also includes the fact that one or more atoms in the compound of formula (I) are replaced by atoms having an atomic mass or mass number different from the atomic mass or mass number normally found in nature. Isotope-labeled compounds, and pharmaceutically acceptable salts thereof are also included in the present invention. Examples of isotopes contained in the compounds of the present invention are hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, bromine, and chlorine isotopes such as ² H, ³ H, ¹¹ C, ¹³ C, ¹⁴ C, ^It includes isotopes such as ¹³ N, ¹⁵ N, ¹⁵ O, ¹⁷ O, ¹⁸ O, ¹⁸ F, ⁷⁵ Br, ⁷⁶ Br, ⁷⁷ Br, ⁸² Br, and ³⁶ Cl. Also included in the present invention are compounds of the present invention that contain the aforementioned isotopes and / or other isotopes of other atoms, and pharmaceutically acceptable salts thereof.

Furthermore, replacement with deuterium, a heavy isotope such as ² H, can be expected to provide certain therapeutic benefits due to increased metabolic stability. For example, it may be preferred in some situations because it results in increased half-life in vivo or reduced dose requirements.

Pharmaceutically acceptable salts include acid addition salts and base addition salts.
Examples of the acid addition salt include inorganic acid salts such as hydrochloride, hydrobromide, sulfate, hydrogen sulfate, hydroiodide, nitrate and phosphate; citrate, oxalate and acetic acid Salt, formate, propionate, benzoate, trifluoroacetate, fumarate, maleate, malonate, succinate, tartrate, hydrogen tartrate, lactate, malate, pyruvate Salt, gluconate, saccharate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, pamoate [1,1′-methylene-bis- (2-hydroxy-3-naphthoate) ] Organic acid salt, such as].
Examples of the base addition salt include inorganic base salts such as sodium salt, potassium salt, calcium salt, magnesium salt and ammonium salt; organic base salts such as triethylammonium salt, triethanolammonium salt, pyridinium salt and diisopropylammonium salt. Can be mentioned.
Furthermore, basic amino acid salts or acidic amino acid salts such as arginine salt, aspartate and glutamate can also be mentioned.
Preferred base addition salts include sodium, potassium, calcium and magnesium salts.

  The compound represented by the formula (I) or a pharmaceutically acceptable salt thereof may exist in the form of a hydrate and / or a pharmaceutically acceptable solvate. Also included in the compounds of the present invention are solvates such as hydrates or ethanolates. Furthermore, the compounds of the present invention include all forms of crystal forms.

[Production method]
Hereinafter, the method for producing the compound represented by the formula (I) in the present invention will be described with reference to examples, but the present invention is not limited thereto.

  The compound of the present invention represented by the formula (I) is produced by the following method using a commercially available compound, a known compound, or a commercially available compound or a compound that can be produced by combining known synthesis methods from known compounds as raw materials. be able to.

[Production Method 1]
Among the compounds represented by the formula (I), the compound represented by the formula (A1) can be produced, for example, by the following production method.

（式中、Ｘ^ａ、Ｘ^ｂ、Ｘ^ｃ、Ｘ^ｄ、Ｙ^ａ、Ｙ^ｂ、Ｙ^ｃ、Ｙ^ｄおよびＹ^ｅは、前記〔１〕に定義されるとおりであり、Ｐ^１はアルキル等のカルボン酸の保護基である。）

(Wherein, X ^a , X ^b , X ^c , X ^d , Y ^a , Y ^b , Y ^c , Y ^d and Y ^e are as defined in the above [1], and P ¹ is alkyl or the like (Protecting group for carboxylic acid.)

  The benzenes (a1) and acetophenones (a3) can be purchased, for example, as commercial products, and the indoles (a4) can be produced by the method described in Org. Synth. 1985, 63, 214, etc. It can be purchased as a product.

[Step A-1]
This step is a step of obtaining compound (a2) by reacting maleic anhydride with compound (a1) in the presence of various acids, in the absence of a solvent, or in a suitable solvent. Examples of the acid used in this step include Lewis acids such as metal halides, Bronsted acids such as phosphoric acid, polyphosphoric acid, and trifluoromethanesulfonic acid, preferably aluminum chloride and iron (III) chloride, Titanium chloride (IV) is mentioned. Examples of the solvent used in this step include aromatic hydrocarbons such as nitrobenzene, halogenated hydrocarbons such as methylene chloride, 1,2-dichloroethane, chloroform, and carbon tetrachloride, or a mixed solvent thereof. And methylene chloride is preferable. The reaction time is usually 5 minutes to 48 hours, preferably 10 minutes to 24 hours. The reaction temperature is generally −78 ° C. to 150 ° C., preferably −20 ° C. to 100 ° C.

[Step A-2]
This step is a step of obtaining compound (a2) by reacting glyoxylic acid with compound (a3) in the presence of various acids, in the absence of a solvent, or in a suitable solvent. Examples of the acid used in this step include Bronsted acids such as acetic acid, phosphoric acid, hydrochloric acid and sulfuric acid, and preferably include acetic acid and hydrochloric acid. Examples of the solvent include ethers such as 1,4-dioxane, water, or a mixed solvent thereof. The reaction time is usually 5 minutes to 48 hours, preferably 10 minutes to 24 hours. The reaction temperature is generally −20 ° C. to 150 ° C., preferably 20 ° C. to 100 ° C.

[Step A-3]
In this step, compound (a2) obtained in step A-1 or A-2 is reacted with indole compound (a4) in a suitable solvent in the presence or absence of various acids. This is a step of obtaining (A1). Examples of the acid used in this step include Bronsted acid such as acetic acid, Lewis acid such as aluminum chloride, iron chloride (III) and titanium chloride (IV), preferably acetic acid and chloride. Iron (III) is mentioned. Solvents used in this step are, for example, aromatic hydrocarbons such as toluene and benzene, aliphatic hydrocarbons such as hexane and heptane, halogenated compounds such as methylene chloride, chloroform and 1,2-dichloroethane. Examples thereof include hydrocarbons or a mixed solvent thereof, preferably benzene or toluene. The reaction time is usually 0.5 hours to 48 hours, preferably 1 hour to 24 hours. The reaction temperature is usually −20 ° C. to 150 ° C., preferably 20 ° C. to 130 ° C.

[Step A-4]
This step is a step of protecting the compound (a2) obtained in the step A-1 or A-2 with P ¹ . This step can be carried out according to the method described in Protective Groups in Organic Synthesis (Theodora W. Greene, Peter GM Wuts, John Wiley & Sons, Inc., 1999).

  For example, compound (a5) can be produced as an ester by reacting compound (a2) with an alcohol in the presence of an acid, in the absence of a solvent, or in a suitable solvent. The solvent used in this step is selected depending on the type of raw material compound and the like, and examples thereof include aromatic hydrocarbons such as toluene and benzene. Examples of the acid used in this step include Bronsted acid such as hydrochloric acid, sulfuric acid, hydrofluoric acid, trifluoroacetic acid, methanesulfonic acid, trifluoromethanesulfonic acid and p-toluenesulfonic acid, boron fluoride etherate, and the like. Of Lewis acids. The reaction time is usually 0.5 hours to 48 hours, preferably 1 hour to 24 hours. The reaction temperature is usually −20 ° C. to 150 ° C., preferably 20 ° C. to 130 ° C.

  For example, the compound (a5) can be produced as an ester by reacting the compound (a2) with an alkyl halide in the presence of various bases in an appropriate solvent or without a solvent. The solvent used in this step is selected depending on the type of raw material compound, etc., for example, ethers such as tetrahydrofuran, 1,4-dioxane and 1,2-dimethoxyethane, and aromatics such as toluene and benzene. Examples thereof include hydrocarbons, amides such as N, N-dimethylformamide and N-methyl-2-pyrrolidone, sulfoxides such as dimethyl sulfoxide, and mixed solvents of these solvents. Examples of the base used in this step include alkali metal hydroxides such as sodium hydroxide, potassium hydroxide and lithium hydroxide, and alkali metal carbonates such as sodium carbonate, potassium carbonate and lithium carbonate. The reaction time is usually 0.5 hours to 48 hours, preferably 1 hour to 24 hours. The reaction temperature is generally −20 ° C. to 150 ° C., preferably 20 ° C. to 100 ° C.

  For example, the compound (a5) can be produced as an ester by reacting the compound (a2) with a diazo compound such as diazomethane or trimethylsilyldiazomethane in the presence of various inorganic salts in an appropriate solvent or without a solvent. . The solvent used in this step is selected depending on the type of raw material compound, etc., for example, ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, or a mixed solvent thereof. Is mentioned. The reaction time is usually 1 minute to 48 hours, preferably 10 minutes to 5 hours. The reaction temperature is usually −20 ° C. to 50 ° C., preferably 0 ° C. to 40 ° C.

[Step A-5]
This step is a step of converting the compound (a5) obtained in the step A-4 into the compound (a6) under the conditions according to the step A-3.

[Step A-6]
This step is a step for preparing the compound obtained in the above A-5 a protecting group P ¹ of (a6) is deprotected to a carboxylic acid (A1). This step is performed by reacting compound (a6) in an appropriate solvent under acidic or basic conditions. The solvent used in this step is selected depending on the type of raw material compound, etc. For example, alcohols such as methanol, ethanol and isopropanol, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane and the like. Examples thereof include ethers, amides such as N, N-dimethylformamide and N-methyl-2-pyrrolidone, sulfoxides such as dimethyl sulfoxide, water, and a mixed solvent thereof. Examples of the acid used in this step include Bronsted acids such as hydrochloric acid and sulfuric acid. Examples of the base used in this step include alkali metal hydroxides such as sodium hydroxide, potassium hydroxide and lithium hydroxide, and alkali metal carbonates such as sodium carbonate, potassium carbonate and lithium carbonate. The reaction time is usually 0.5 hours to 48 hours, preferably 1 hour to 24 hours. The reaction temperature is usually 0 ° C to 150 ° C, preferably 20 ° C to 100 ° C.

[Production Method 2]
Among the compounds represented by the formula (I), the compound represented by the formula (A2) can be produced, for example, by the following production method.

（式中、Ｘ^ａ、Ｘ^ｂ、Ｘ^ｃ、Ｘ^ｄ、Ｙ、Ａは、前記〔１〕に定義されるとおりであり、Ｐ^１はカルボン酸の保護基であり、Ｐ^２はアミノ基の保護基であり、ＬＧは脱離基（例えば塩素、臭素、ヨウ素のようなハロゲン原子、メタンスルホニルオキシ基のようなアルキルスルホニルオキシ基、トリフルオロメタンスルホニルオキシ基のようなトリハロゲノメタンスルホニルオキシ基、ベンゼンスルホニルオキシ基、ｐ−トルエンスルホニルオキシ基のようなアリールスルホニルオキシ基など）である。）

(Wherein, X ^a , X ^b , X ^c , X ^d , Y, A are as defined in [1] above, P ¹ is a protecting group for carboxylic acid, and P ² is an amino group. LG is a protecting group, and LG is a leaving group (for example, a halogen atom such as chlorine, bromine or iodine, an alkylsulfonyloxy group such as methanesulfonyloxy group, a trihalogenomethanesulfonyloxy group such as trifluoromethanesulfonyloxy group, Benzenesulfonyloxy group, arylsulfonyloxy group such as p-toluenesulfonyloxy group, etc.).

  Indole acetic acid (a7) can be produced, for example, by the method described in US Patent Application Publication No. 5684034 and the like, or can be purchased as a commercial product, and compound (a9) is, for example, It can be produced by the method described in Journal of the Chemical Society-Perkin Transactions 1, 1996, 2303-2308, Journal of Organic Chemistry, 1984, 438-442, and the like, or can be purchased as a commercial product. .

[Step A-7]
This step is a step of introducing a protecting group P ² into the compound (a7). This step can be carried out according to the method described in Protective Groups in Organic Synthesis (Theodora W. Greene, Peter GM Wuts, John Wiley & Sons, Inc., 1999).

  When a tert-butoxycarbonyl group is introduced, compound (a8) can be produced by reacting compound (a7) with di-tert-butyl dicarbonate in a suitable solvent in the presence of a base.

  When a benzyloxycarbonyl group is introduced, compound (a8) can be produced by reacting compound (a7) with benzyloxycarbonyl chloride in a suitable solvent in the presence of a base.

  When a p-toluenesulfonyl group is introduced, compound (a8) can be produced by reacting compound (a7) with p-toluenesulfonyl chloride in a suitable solvent in the presence of a base.

  Examples of the solvent used in this step include halogenated hydrocarbons such as methylene chloride and chloroform, ethers such as tetrahydrofuran and 1,4-dioxane, N, N-dimethylformamide, N-methyl-2- Amides such as pyrrolidone, water or a mixed solvent thereof can be mentioned, and tetrahydrofuran, methylene chloride and N, N-dimethylformamide are preferred. Examples of the base used in this step include alkali carbonates such as sodium carbonate and potassium carbonate, alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, triethylamine, diisopropylethylamine, pyridine, and 4-dimethylamino. Organic bases such as pyridine and 1,8-diazabicyclo [5.4.0] -undec-7-ene are exemplified, and triethylamine, diisopropylethylamine and 4-dimethylaminopyridine are preferred. The reaction time is usually 5 minutes to about 48 hours, preferably 10 minutes to 10 hours. The reaction temperature is generally −78 ° C. to 100 ° C., preferably −20 ° C. to 40 ° C.

[Step A-8]
In this step, compound (a10) is reacted with compound (a9) in the presence of an additive in the presence or absence of an additive in a suitable solvent and compound (a8) obtained in step A-7. ). Examples of the solvent used in this step include ethers such as tetrahydrofuran and 1,4-dioxane, amides such as N, N-dimethylformamide and N-methyl-2-pyrrolidone, and mixed solvents thereof. Preferably, tetrahydrofuran and N, N-dimethylformamide are used. Examples of the base used in this step include organometallic bases such as butyl lithium, lithium diisopropylamide, and lithium hexamethyldisilazide, preferably lithium hexamethyldisilazide and lithium diisopropylamide, and more preferably. Examples include lithium hexamethyldisilazide. Examples of the additive used when necessary in this step include hexamethyl phosphate triamide and N, N-dimethylpropylene urea, and more preferably hexamethyl phosphate triamide. The reaction time is usually 5 minutes to 48 hours, preferably 10 minutes to 24 hours. The reaction temperature is generally −78 ° C. to 100 ° C., preferably −78 ° C. to 20 ° C.

[Step A-9]
This step is the A-8 The compound obtained in step a protective group P ² of (a10), by deprotection, to produce compound (a11). This step can be carried out according to the method described in Protective Groups in Organic Synthesis (Theodora W. Greene, Peter GM Wuts, John Wiley & Sons, Inc., 1999).

When the protecting group P ² is a tert-butoxycarbonyl group, the compound (a10) is subjected to Bronsted acid such as hydrochloric acid, sulfuric acid, trifluoroacetic acid, or aluminum chloride, zinc bromide, trifluoride in a suitable solvent. Compound (a11) can be produced by using a Lewis acid such as boron. Solvents used in this step are, for example, ethers such as tetrahydrofuran, diethyl ether, 1,4-dioxane, 1,2-dimethoxyethane, aromatic hydrocarbons such as toluene and benzene, methylene chloride, chloroform. , Halogenated hydrocarbons such as 1,2-dichloroethane, mixed solvents thereof and the like. In the case of Bronsted acid, water can be used alone or mixed with the described solvent. The reaction time is usually 0.5 hours to 48 hours, preferably 0.5 hours to 24 hours. The reaction temperature is usually −20 ° C. to 100 ° C., preferably −20 ° C. to 40 ° C.

When the protecting group P ² is a benzyloxycarbonyl group, the compound (a10) can be used in an appropriate solvent, for example, in the presence of a metal catalyst such as palladium / carbon, palladium hydroxide, nickel, and ammonium formate if necessary. Can be added and reacted in a hydrogen gas atmosphere to produce the compound (a11). Examples of the solvent used in this step include alcohols such as methanol, ethanol and isopropanol, ethers such as tetrahydrofuran and 1,4-dioxane, aromatic hydrocarbons such as toluene and benzene, hexane and heptane. Aliphatic hydrocarbons such as, esters such as ethyl acetate and propyl acetate, organic acids such as acetic acid, and mixed solvents thereof.

[Step A-10]
This step is a step of producing compound (A2) from the compound (a11) obtained in the above step A-9 by the same method as in the above step A-6.

According to the production method shown above, for example, the following compounds can be synthesized.
4- (4-Chlorophenyl) -2- (5-fluoro-1H-indol-3-yl) -4-oxobutanoic acid 4- (4-chlorophenyl) -2- (6-fluoro-1H-indole- 3-yl) -4-oxobutanoic acid 2- (4-chloro-1H-indol-3-yl) -4- (4-chlorophenyl) -4-oxobutanoic acid 4- (4-chlorophenyl) 2- (5-Fluoro-1H-indol-3-yl) -4-oxobutanoic acid 2- (5-chloro-1H-indol-3-yl) -4- (4-chlorophenyl) -4- Oxobutanoic acid 4- (4-chlorophenyl) -2- (5-methyl-1H-indol-3-yl) -4-oxobutanoic acid 4- (4-chlorophene) ) -2- (6-Methyl-1H-indol-3-yl) -4-oxobutanoic acid 4- (4-chlorophenyl) -2- (7-methyl-1H-indol-3-yl)- 4-oxobutanoic acid 4- (4-chlorophenyl) -2- (5-ethyl-1H-indol-3-yl) -4-oxobutanoic acid 4- (4-chlorophenyl) -2- (5 -Methoxy-1H-indol-3-yl) -4-oxobutanoic acid 4- (4-chlorophenyl) -2- (6-methoxy-1H-indol-3-yl) -4-oxobutanoic acid 4- (3-Chlorophenyl) -2- (5-fluoro-1H-indol-3-yl) -4-oxobutanoic acid 4- (3-chlorophenyl) -2- (6-fur Oro-1H-indol-3-yl) -4-oxobutanoic acid 4- (3-chlorophenyl) -2- (6-methyl-1H-indol-3-yl) -4-oxobutanoic acid 4 -(3-Chlorophenyl) -2- (6-methoxy-1H-indol-3-yl) -4-oxobutanoic acid 2- (5-fluoro-1H-indol-3-yl) -4- (4 -Methylphenyl) -4-oxobutanoic acid 2- (6-fluoro-1H-indol-3-yl) -4- (4-methylphenyl) -4-oxobutanoic acid 2- (5-chloro) -1H-indol-3-yl) -4- (4-methylphenyl) -4-oxobutanoic acid 2- (6-chloro-1H-indol-3-yl) -4- (4-me Tylphenyl) -4-oxobutanoic acid 2- (5-methyl-1H-indol-3-yl) -4- (4-methylphenyl) -4-oxobutanoic acid 4- (4-methylphenyl) -4-oxo-2- [5- (propan-2-yl) -1H-indol-3-yl] butanoic acid 2- (5-methoxy-1H-indol-3-yl) -4- (4-methyl) Phenyl) -4-oxobutanoic acid 2- (6-methoxy-1H-indol-3-yl) -4- (4-methylphenyl) -4-oxobutanoic acid 4- (3-tert-butyl) Phenyl) -2- (5-fluoro-1H-indol-3-yl) -4-oxobutanoic acid 4- (3-tert-butylphenyl) -2- (6-fluoro -1H-Indol-3-yl) -4-oxobutanoic acid 4- (3-tert-butylphenyl) -2- (5-chloro-1H-indol-3-yl) -4-oxobutanoic Acid 4- (3-tert-butylphenyl) -2- (6-chloro-1H-indol-3-yl) -4-oxobutanoic acid 4- (3-tert-butylphenyl) -2- (5 -Methyl-1H-indol-3-yl) -4-oxobutanoic acid 4- (3-tert-butylphenyl) -2- (5-methoxy-1H-indol-3-yl) -4-oxobuta Neuc acid 4- (4-chloro-2-fluorophenyl) -2- (5-chloro-1H-indol-3-yl) -4-oxobutanoic acid 4- (4-c (Ro-2-fluorophenyl) -2- (6-chloro-1H-indol-3-yl) -4-oxobutanoic acid 4- (4-chloro-2-fluorophenyl) -2- (5-methyl) -1H-indol-3-yl) -4-oxobutanoic acid 4- (4-chloro-2-fluorophenyl) -2- (6-methyl-1H-indol-3-yl) -4-oxobuta Neucic acid 4- (4-chloro-2-fluorophenyl) -4-oxo-2- [5- (propan-2-yl) -1H-indol-3-yl] butanoic acid 2- (5-chloro- 1H-Indol-3-yl) -4- (4-chloro-2-methylphenyl) -4-oxobutanoic acid 2- (6-chloro-1H-indol-3-yl) -4- (4- Black -2-Methylphenyl) -4-oxobutanoic acid 4- (4-chloro-2-methylphenyl) -2- (5-methyl-1H-indol-3-yl) -4-oxobutanoic acid 4- (4-Chloro-2-methylphenyl) -2- (6-methyl-1H-indol-3-yl) -4-oxobutanoic acid 4- (4-chloro-2-methylphenyl) -4 -Oxo-2- [5- (propan-2-yl) -1H-indol-3-yl] butanoic acid 2- (5-chloro-1H-indol-3-yl) -4- (2-fluoro-4 -Methylphenyl) -4-oxobutanoic acid 2- (6-chloro-1H-indol-3-yl) -4- (2-fluoro-4-methylphenyl) -4-oxobutanoic acid 2- (5-Chloro-1H-indol-3-yl) -4- (2-chloro-4-methylphenyl) -4-oxobutanoic acid 2- (6-chloro-1H-indole-3- Yl) -4- (2-chloro-4-methylphenyl) -4-oxobutanoic acid

  The compound of the present invention represented by formula (I) or an intermediate thereof can be separated and purified by methods known to those skilled in the art. For example, extraction, distribution, reprecipitation, column chromatography (for example, silica gel column chromatography, ion exchange column chromatography or preparative liquid chromatography) or recrystallization may be mentioned.

  Examples of the recrystallization solvent include alcohol solvents such as methanol, ethanol and isopropanol, ether solvents such as diethyl ether, ester solvents such as ethyl acetate, aromatic hydrocarbon solvents such as benzene and toluene, acetone and the like. A ketone solvent, a halogen solvent such as dichloromethane or chloroform, a hydrocarbon solvent such as hexane, an aprotic solvent such as N, N-dimethylformamide or acetonitrile, water, or a mixed solvent thereof can be used. As other purification methods, methods described in Experimental Chemistry Course (The Chemical Society of Japan, Maruzen) 5th edition, Volume 1 and the like can be used. Further, the molecular structure of the compound of the present invention is determined by referring to the structure derived from each raw material compound, a spectroscopic method such as nuclear magnetic resonance method, infrared absorption method, circular dichroism spectrum analysis method, and the like. Can be done by mass spectrometry.

  In addition, the intermediate or final product in the above production method is appropriately converted in its functional group, in particular, extending various side chains based on amino groups, hydroxyl groups, carbonyl groups, halogen groups, etc., and In this case, if necessary, the above-mentioned protection and deprotection can be performed to lead to another compound included in the present invention. The transformation of the functional group and the extension of the side chain can be performed by a commonly used general method (for example, see Comprehensive Organic Transformations, RC Larock, John Wiley & Sons Inc. (1999)).

  The compound of the present invention represented by the formula (I) or a pharmaceutically acceptable salt thereof may have asymmetry or may have a substituent having an asymmetric carbon. Has optical isomers. The compounds of the present invention include mixtures of these isomers and isolated ones. Examples of the production method include a method using a raw material having an asymmetric point, or a method of introducing asymmetry at an intermediate stage. Alternatively, for example, an optical isomer can be obtained by performing a separation step such as a method using an optically active column or a fractional crystallization method at an appropriate stage of the production process. As the optical resolution method, for example, when the compound represented by the formula (I) or an intermediate thereof has a basic functional group, it is used in an inert solvent (for example, an alcohol solvent such as methanol, ethanol, isopropanol, diethyl An ether solvent such as ether, an ester solvent such as ethyl acetate, a hydrocarbon solvent such as toluene, an aprotic solvent such as acetonitrile, water or a mixed solvent of two or more selected from the above solvents), optically active Acids (for example, monocarboxylic acids such as mandelic acid, N-benzyloxyalanine and lactic acid, tartaric acid, o-diisopropylidene tartaric acid, dicarboxylic acids such as malic acid, sulfonic acids such as camphorsulfonic acid and bromocamphorsulfonic acid) And a diastereomeric method in which a salt is formed. When the compound of the present invention represented by formula (I) or an intermediate thereof has an acidic functional group such as a carboxyl group, an optically active amine (for example, 1-phenylethylamine, quinine, quinidine, cinchonidine, cinchonine, strychnine) The optical resolution can also be carried out by forming a salt using an organic amine).

  The temperature at which the salt is formed is selected from the range from −50 ° C. to the boiling point of the solvent, preferably from 0 ° C. to the boiling point, more preferably from room temperature to the boiling point of the solvent. In order to improve the optical purity, it is often desirable to raise the temperature to near the boiling point of the solvent once. When the precipitated salt is collected by filtration, it can be cooled as necessary to improve the yield. The amount of the optically active acid or amine used is in the range of about 0.5 to about 2.0 equivalents, preferably in the range of about 1 equivalent, relative to the substrate. If necessary, a salt in an inert solvent (for example, an alcohol solvent such as methanol, ethanol, isopropanol, an ether solvent such as diethyl ether, an ester solvent such as ethyl acetate, a hydrocarbon solvent such as toluene, a non-aqueous solvent such as acetonitrile, etc. It can also be recrystallized with a proton solvent or a mixed solvent of two or more selected from the above-mentioned solvents to obtain a highly pure optically active salt. Further, if necessary, the optically resolved salt can be treated with an acid or a base by a usual method to obtain the optically active compound of the present invention represented by formula (I) as a free form.

  Among the raw materials and intermediates in each of the production methods described above, those that do not describe the production method are commercially available compounds, or methods known to those skilled in the art from commercially available compounds, or methods equivalent thereto Can be synthesized.

  Since the compound of the present invention has an action for improving mitochondrial function, it can provide a therapeutic or prophylactic agent for diseases or symptoms involving mitochondrial dysfunction. More specifically, it is useful as a therapeutic and / or prophylactic agent for mitochondrial diseases, neurodegenerative diseases, immune neurological diseases, cerebral ischemic diseases, renal diseases, muscle diseases, or heart diseases.

  In the present invention, “prevention” is an act of administering the active ingredient of the present invention to a person who has not developed a disease. For example, the purpose is to prevent or delay the onset of the disease. Is. “Treatment” is an act of administering the active ingredient of the present invention to a person (patient) diagnosed as having developed a disease by a doctor.

  Mitochondrial disease is a disease in which a decrease in mitochondrial function such as ATP production, regulation of apoptosis, regulation of intracellular concentrations of calcium ions and iron, etc. occurs due to mutation or deletion of nuclear DNA or mitochondrial DNA.

  One of the symptoms of mitochondrial diseases that can be treated or prevented by the compound of the present invention is Leigh's encephalopathy. Leigh's encephalopathy is a serious congenital disease that begins in early childhood and is characterized by symmetric degeneration of the basal ganglia and brainstem, with intellectual disability, muscle movement disorder, and respiratory disorder as the main symptoms.

  Other symptoms of mitochondrial diseases that can be treated or prevented by the compounds of the present invention include, for example, mitochondrial encephalomyopathy, lactic acidosis, stroke-like seizure syndrome (MELAS), chronic progressive extraocular muscular palsy syndrome (CPEO), Kearns Sayre Syndrome (KSS), myoclonic epilepsy syndrome with red rag fibers (MERRF), Pearson's disease, Leber hereditary optic neuropathy (LHON), mitochondrial encephalomyopathy, Bath syndrome, lactic acidosis and the like.

  Examples of neurodegenerative diseases that can be treated or prevented by the compounds of the present invention include amyotropic axillary lateral sclerosis (ALS), Parkinson's disease, Alzheimer's disease, Huntington's disease, Friedreich's ataxia, multiple system atrophy, progressive nuclear supra Include paralysis, spinocerebellar degeneration, spinal muscular atrophy, bulbar spinal muscular atrophy, Charcot-Marie-Tooth disease.

  Examples of immune neurological diseases that can be treated or prevented by the compounds of the present invention include Guillain-Barre syndrome, multiple sclerosis, Fischer syndrome, chronic inflammatory demyelinating polyneuritis, myasthenia gravis.

  Examples of cerebral ischemic diseases that can be treated or prevented by the compound of the present invention include cerebral infarction and the like.

  Examples of renal diseases that can be treated or prevented by the compound of the present invention include renal failure, amyloid kidney, membranous nephropathy, focal glomerulosclerosis, IgA nephropathy, acute tubular necrosis, nephrotic syndrome, diabetic nephropathy, Examples include gout kidney, renal edema, renal tumor, renal ischemic injury, renal ischemia reperfusion injury, cystic kidney and the like.

  Examples of the muscular disease that can be treated or prevented by the compound of the present invention include progressive muscular dystrophy, myotonic dystrophy, congenital myopathy, metabolic myopathy, distal myopathy, inflammatory myopathy, age-related muscle atrophy (Sarcopenia), Examples include disuse muscle atrophy.

  Examples of the heart disease that can be treated or prevented by the compound of the present invention include myocardial infarction, heart failure, ischemic heart disease, cardiomyopathy and the like.

  The administration route of the compound of the present invention may be any of oral administration, parenteral administration and rectal administration, and the daily dose varies depending on the type of compound, administration method, patient symptom / age and the like. For example, in the case of oral administration, about 0.01 mg to 5000 mg, more preferably about 0.1 mg to 3000 mg per kg body weight of a human or mammal can be administered in 1 to several times. In the case of parenteral administration such as intravenous injection, usually, for example, about 0.01 mg to 300 mg, more preferably about 1 mg to 100 mg per kg body weight of a human or mammal can be administered.

The compound of the present invention can be formulated and administered by oral administration or parenteral administration, directly or using a suitable dosage form. Examples of the dosage form include, but are not limited to, tablets, capsules, powders, granules, solutions, suspensions, injections, patches, and haptics. The preparation is produced by a known method using a pharmaceutically acceptable additive.
Additives are excipients, disintegrants, binders, fluidizers, lubricants, coating agents, solubilizers, solubilizers, thickeners, dispersants, stabilizers, sweeteners depending on the purpose. Perfumes and the like can be used. Specifically, for example, lactose, mannitol, crystalline cellulose, low-substituted hydroxypropyl cellulose, corn starch, partially pregelatinized starch, carmellose calcium, croscarmellose sodium, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinyl alcohol, stearin Examples include magnesium acid, sodium stearyl fumarate, polyethylene glycol, propylene glycol, titanium oxide, and talc.

  Examples of other drugs that can be used in combination with the compound of the present invention include mitochondrial function improving agents, neurodegenerative disease therapeutic agents, muscle disease therapeutic agents, cardiac disease therapeutic agents, and renal disease therapeutic agents.

  Examples of the mitochondrial function improving agent include Bendavia and idebenone.

  Examples of therapeutic agents for neurodegenerative diseases include ALS therapeutic agents (riluzole, edaravone, etc.), Parkinson's disease therapeutic agents (levodopa, carbidopa, zonisamide, droxidopa, pramipexole, ropinirole, etc.), Alzheimer's disease therapeutic agents (donepezil, memantine, rivastigmine, Galantamine, etc.).

  Examples of the muscular disease therapeutic agent include anti-activin antibodies (such as bimaglumumab) and steroidal anti-inflammatory drugs (such as prednisolone and triamcinolone).

  Examples of therapeutic agents for heart diseases and kidney diseases include angiotensin II receptor antagonists (candesartan, valsartan, etc.), ACE inhibitors (captopril, enalapril, etc.), diuretics (furosemide, tolvaptan, etc.) and the like.

  In the combination of the compound of the present invention or a pharmaceutically acceptable salt thereof and other drugs that can be used in combination, the plurality of drugs may be administered separately or may be administered together as a single pharmaceutical composition. . Also, one active ingredient of the combination of the present invention may be administered prior to, simultaneously with, or after other active ingredients. These active ingredients may be prepared in a pharmaceutical formulation in a single dosage form or in a separate dosage form.

  Hereinafter, the present invention will be described more specifically with reference examples, examples, and test examples, but the present invention is not limited thereto. In addition, the compound names shown in the following Reference Examples and Examples do not necessarily follow the IUPAC nomenclature.

In order to simplify the description, the following abbreviations may be used in the reference examples and examples.
Me: methyl
^t Bu: tert-butyl TFA: trifluoroacetic acid THF: tetrahydrofuran DMSO: dimethyl sulfoxide DMSO-D ₆ : deuterated dimethyl sulfoxide Boc: tert-butoxycarbonyl (Boc) ₂ O: di-tert-butyl dicarbonate DMAP: 4-dimethyl Aminopyridine LHMDS: Lithium hexamethyldisilazide HMPA: Hexamethyl phosphate triamide

  As symbols used in NMR, s is a single line, d is a double line, dd is a double double line, t is a triple line, q is a quadruple line, m is a multiple line, br is wide, brs is Wide single line and J mean coupling constant.

  The proton nuclear magnetic resonance spectrum was measured using a FT-NMR measuring apparatus (270 MHz, 300 MHz or 400 MHz) manufactured by JEOL. The chemical shift value was described in δ value (ppm).

High-performance liquid chromatograph / mass spectrometer; LCMS measurement conditions are as follows, and the observed mass spectrometry value [MS (m / z)] is represented by [M + H] ⁺ and the retention time is represented by Rt (min). . In each actual measurement value, the measurement conditions used for measurement are indicated by A and B.

[Measurement condition A]
Detection equipment: Shimadzu LCMS-2020
Column: Phenomenex Kinex (1.7 μm C18, 50 mm × 2.10 mm)
Solvent: Liquid A: 0.05% TFA / H ₂ O, Liquid B: CH ₃ CN
Gradient Condition:
0.0-1.7 min; A / B = 90: 10 to 1:99 (liner gradient)
1.7-1.9 min; A / B = 1: 99
1.9-3.0 min; A / B = 90: 10
Flow rate: 0.5 mL / min UV: 220 nm
Column temperature: 40 ° C

[Measurement condition B]
Measuring instrument: Waters 2695
Column: Yamato Science Prima Sil C18HC (5 μm, 4.6 × 75 mm)
Solvent: A solution: 0.1% formic acid / H ₂ O, B solution: 0.1% formic acid / CH ₃ CN
Gradient Condition:
0.0-6.0 min; A / B = 90: 10 to 0: 100 (liner gradient)
6.0-8.0 min; A / B = 0: 100
Flow rate: 1.0 mL / min UV: 220, 254 nm
Column temperature: 40 ° C

[Reference Example 1]
Preparation of methyl 2- (6-chloro-1H-indol-3-yl) -4- (2,4-difluorophenyl) -4-oxobutanoate (compound III)

化合物Ｉ（５００ｍｇ）のトルエン（４．９ｍＬ）溶液に化合物II（３６９ｍｇ）と塩化鉄（III）６水和物（１２０ｍｇ）を加え、９０℃で１．５時間撹拌した。溶媒を減圧留去後、得られた残査をシリカゲルカラムクロマトグラフィー（溶出溶媒：ヘキサン／酢酸エチル）で精製し、表題化合物III（３３２ｍｇ）を得た。
ＬＣ−ＭＳ：測定法Ｂ、[M+H]^＋=378.2、Rt=6.46min

Compound II (369 mg) and iron (III) chloride hexahydrate (120 mg) were added to a solution of compound I (500 mg) in toluene (4.9 mL), and the mixture was stirred at 90 ° C. for 1.5 hours. After the solvent was distilled off under reduced pressure, the obtained residue was purified by silica gel column chromatography (elution solvent: hexane / ethyl acetate) to obtain the title compound III (332 mg).
LC-MS: Measurement method B, [M + H] ⁺ = 378.2, Rt = 6.46min

[Reference Examples 2 to 6]
The compounds of Reference Examples 2 to 6 were obtained in the same manner as in Reference Example 1 using the corresponding starting compounds.

[Reference Example 7]
Preparation of tert-butyl 3- [4- (2-chlorophenyl) -1-methoxy-1,4-dioxobutan-2-yl] -1H-indole-1-carboxylate (Compound III-1)

−７８℃の化合物Ｉ−１（４００ｍｇ）、ＨＭＰＡ（０．４８ｍＬ）とＴＨＦ（１４ｍＬ）の混合物に、ＬＨＭＤＳ／ＴＨＦ溶液（１．３ｍｏｌ／Ｌ、１．３ｍＬ）を加え、−７８℃にて１．５時間撹拌した。−７８℃の混合溶液に、化合物II−１（３９１ｍｇ）のＴＨＦ溶液（５ｍＬ）を滴下して加えた後、室温にて１２時間撹拌した。水を加えた後、酢酸エチルで分液抽出し、有機層を２ｍｏｌ／Ｌ塩酸、飽和食塩水の順に洗浄し、無水硫酸ナトリウムで乾燥後、減圧濃縮した。得られた残査をシリカゲルカラムクロマトグラフィー（溶出溶媒：ヘキサン／酢酸エチル）で精製し、表題化合物III−１（１７５ｍｇ）を得た。
ＬＣ−ＭＳ：測定法Ｂ、[M+H]^＋=442.3、Rt=7.40min

To a mixture of compound I-1 (400 mg), HMPA (0.48 mL) and THF (14 mL) at −78 ° C., an LHMDS / THF solution (1.3 mol / L, 1.3 mL) was added, and at −78 ° C. Stir for 1.5 hours. To a mixed solution at −78 ° C., a THF solution (5 mL) of compound II-1 (391 mg) was added dropwise, followed by stirring at room temperature for 12 hours. Water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with 2 mol / L hydrochloric acid and saturated brine in that order, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate) to give the title compound III-1 (175 mg).
LC-MS: Method B, [M + H] ⁺ = 442.3, Rt = 7.40min

[Reference Examples 8 to 10]
The compounds of Reference Examples 8 to 10 were obtained in the same manner as in Reference Example 7 using the corresponding starting compounds.

[Reference Example 11]
Preparation of tert-butyl 3- (8,8,8-trifluoro-1-methoxy-1-oxooctane-2-yl) -1H-indole-1-carboxylate (compound III-2)

−７８℃のジイソプロピルアミン（０．１９６ｍＬ）のＴＨＦ溶液（２．３ｍＬ）に、ｎ−ブチルリチウムのヘキサン溶液（１ｍｏｌ／Ｌ，１．４ｍＬ）を加えた後、氷冷にて２０分間撹拌した。反応液を−７８℃に冷却し、化合物Ｉ−２（２００ｍｇ）を加え、３０分間撹拌した後、化合物II−２（０．１６７ｍＬ）を添加後、室温において２３時間撹拌した。水を加えた後、酢酸エチルで抽出し、有機層を無水硫酸ナトリウムで乾燥後、減圧濃縮した。得られた残査をシリカゲルカラムクロマトグラフィー（溶出溶媒：ヘキサン／酢酸エチル）で精製し表題化合物III−２（７１ｍｇ）を得た。
ＬＣＭＳ：測定法Ａ、[M+H]^＋=428.2、Rt=2.06min

A hexane solution (1 mol / L, 1.4 mL) of n-butyllithium was added to a THF solution (2.3 mL) of diisopropylamine (0.196 mL) at −78 ° C., followed by stirring for 20 minutes with ice cooling. . The reaction solution was cooled to −78 ° C., compound I-2 (200 mg) was added, and the mixture was stirred for 30 minutes. After addition of compound II-2 (0.167 mL), the mixture was stirred at room temperature for 23 hours. Water was added, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate) to give the title compound III-2 (71 mg).
LCMS: Method A, [M + H] ⁺ = 428.2, Rt = 2.06min

[Example 1]
Preparation of 4- (2,4-dichlorophenyl) -2- (1H-indol-3-yl) -4-oxobutanoic acid (Compound III-3)

化合物Ｉ−３（１．８９ｇ）のトルエン（５９ｍＬ）溶液に化合物II−３（１．１７ｇ）を加えた後、１２時間加熱還流した。室温に冷却し、析出した固体をろ取し、トルエンとヘキサンで洗浄、乾燥し、表題化合物III−３（２．１０ｇ）を得た。
¹H-NMR (270MHz, CD₃OD) δ: 7.66-7.52 (3H, m), 7.42-7.31 (2H, m), 7.17-6.98 (3H, m), 4.50-4.45 (1H, m), 3.96-3.86 (1H, m), 3.39-3.31 (1H, m)

Compound II-3 (1.17 g) was added to a solution of compound I-3 (1.89 g) in toluene (59 mL), and the mixture was heated to reflux for 12 hours. After cooling to room temperature, the precipitated solid was collected by filtration, washed with toluene and hexane, and dried to give the title compound III-3 (2.10 g).
¹ H-NMR (270 MHz, CD ₃ OD) δ: 7.66-7.52 (3H, m), 7.42-7.31 (2H, m), 7.17-6.98 (3H, m), 4.50-4.45 (1H, m), 3.96 -3.86 (1H, m), 3.39-3.31 (1H, m)

[Examples 2 to 29]
The compounds of Examples 2 to 29 were obtained in the same manner as in Example 1 using the corresponding starting compounds.

[Example 30]
Preparation of 2- (6-chloro-1H-indol-3-yl) -4- (2,4-difluorophenyl) -4-oxobutanoic acid (Compound II-4)

化合物III（６２８ｍｇ、参考例１）、ＴＨＦ（２０ｍＬ）、水（１０ｍＬ）、水酸化リチウム一水和物（７７ｍｇ）の混合溶液を、室温にて１２時間撹拌した。４ｍｏｌ／Ｌ塩酸を加えて溶液のｐＨを１にした後、酢酸エチルで分液抽出し、有機層を水で洗浄し、無水硫酸ナトリウムで乾燥後、減圧濃縮した。得られた残査に塩化メチレン（１０ｍＬ）を加え析出した固体をろ取し、塩化メチレンで洗浄、乾燥し、表題化合物II−４（５５２ｍｇ）を得た。
¹H-NMR (270MHz, CD₃OD) δ: 8.01-7.92 (1H, m), 7.63 (1H, d, J = 8.6 Hz), 7.35 (1H, d, J = 1.8 Hz), 7.21 (1H, s), 7.13-6.98 (3H, m), 4.46 (1H, dd, J = 10.4, 4.0 Hz), 4.04-3.88 (1H, m), 3.41-3.28 (1H, m)

A mixed solution of Compound III (628 mg, Reference Example 1), THF (20 mL), water (10 mL), and lithium hydroxide monohydrate (77 mg) was stirred at room temperature for 12 hours. 4 mol / L hydrochloric acid was added to adjust the pH of the solution to 1, followed by liquid separation extraction with ethyl acetate, the organic layer was washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Methylene chloride (10 mL) was added to the resulting residue, and the precipitated solid was collected by filtration, washed with methylene chloride, and dried to give the title compound II-4 (552 mg).
¹ H-NMR (270 MHz, CD ₃ OD) δ: 8.01-7.92 (1H, m), 7.63 (1H, d, J = 8.6 Hz), 7.35 (1H, d, J = 1.8 Hz), 7.21 (1H, s), 7.13-6.98 (3H, m), 4.46 (1H, dd, J = 10.4, 4.0 Hz), 4.04-3.88 (1H, m), 3.41-3.28 (1H, m)

[Examples 31 to 35]
The compounds of Examples 31 to 35 were obtained in the same manner as in Example 30 using the corresponding starting compounds.

[Example 36]
Preparation of 4- (2-chlorophenyl) -2- (1H-indol-3-yl) -4-oxobutanoic acid (compound II-5)

化合物III−１（１７５ｍｇ、参考例７）と塩化水素−１，４−ジオキサン溶液（４ｍｏｌ／Ｌ、３．１ｍＬ）の混合物を、室温にて１２時間撹拌した。次いで、水酸化ナトリウム水溶液（６ｍｏｌ／Ｌ、３．１ｍＬ）、メタノール（３．１ｍＬ）、水（３．１ｍＬ）を加え、室温で４時間撹拌した。反応溶液を減圧濃縮後、塩化メチレンと水を加えた後に、分液抽出した。水層を塩化メチレンで洗浄し、４ｍｏｌ／Ｌ塩酸を加えてｐＨを１とした。塩化メチレンと水で分液抽出し、有機層を無水硫酸ナトリウムで乾燥後、減圧濃縮した。得られた残査をシリカゲルカラムクロマトグラフィー（溶出溶媒：塩化メチレン／メタノール）で精製し表題化合物II−５（７４ｍｇ）を得た。
¹H-NMR (270 MHz, CD₃OD) δ: 7.65 (1H, d, J = 7.4 Hz), 7.54 (1H, d, J = 7.4 Hz), 7.46-7.42 (2H, m), 7.39-7.31 (2H, m), 7.16 (1H, s), 7.13-6.98 (2H, m), 4.48 (1H, dd, J = 10.1, 4.5 Hz), 3.92 (1H, dd, J = 17.9, 10.1 Hz), 3.39-3.31 (1H, m)

A mixture of Compound III-1 (175 mg, Reference Example 7) and hydrogen chloride-1,4-dioxane solution (4 mol / L, 3.1 mL) was stirred at room temperature for 12 hours. Next, an aqueous sodium hydroxide solution (6 mol / L, 3.1 mL), methanol (3.1 mL), and water (3.1 mL) were added, and the mixture was stirred at room temperature for 4 hours. The reaction solution was concentrated under reduced pressure, and methylene chloride and water were added, followed by liquid separation extraction. The aqueous layer was washed with methylene chloride, and 4 mol / L hydrochloric acid was added to adjust the pH to 1. Liquid separation extraction was carried out with methylene chloride and water, and the organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: methylene chloride / methanol) to obtain the title compound II-5 (74 mg).
¹ H-NMR (270 MHz, CD ₃ OD) δ: 7.65 (1H, d, J = 7.4 Hz), 7.54 (1H, d, J = 7.4 Hz), 7.46-7.42 (2H, m), 7.39-7.31 (2H, m), 7.16 (1H, s), 7.13-6.98 (2H, m), 4.48 (1H, dd, J = 10.1, 4.5 Hz), 3.92 (1H, dd, J = 17.9, 10.1 Hz), 3.39-3.31 (1H, m)

[Examples 37 to 40]
The compounds of Examples 37 to 40 were obtained in the same manner as in Example 36 using the corresponding starting compounds.

[Test example]
The pharmacological test results of the representative compounds of the present invention are shown below, but the present invention is not limited to these test examples.

[Test Example 1: Inhibitory effect on cell death due to oxidative stress in KSS patient-derived fibroblasts]
In order to examine the effect of suppressing cell death due to oxidative stress in KSS patient-derived fibroblasts with respect to the compound of the present invention, KSS patient-derived fibroblasts treated with glutathione synthesis inhibitor BSO (L-Buthionine sulphoximine) The cells were cultured in the presence and the cell viability was measured.

[Method]
1.5 × 10 ⁴ KSS patient-derived fibroblasts per well were seeded in a 48-well cell culture plate and then cultured for 24 hours. A glutathione synthesis inhibitor BSO (manufactured by Sigma-Aldrich) was added at 100 μmol / L. It mixed in the culture solution so that it might become. After culturing for 24 hours in the presence of BSO, the Example compounds were mixed in the culture solution to 3 or 10 μmol / L. After culturing for 3 days in the presence of the compound, the number of viable cells was measured using Cell Count Reagent SF (Nacalai Tesque), and the cell viability was calculated. In addition, as a control for the oxidative stress load, a well to which both BSO and the compound were not added was used, and as a control for the effect of the compound, a BSO added well was used.

[result]
Table 6 shows the inhibitory effect of each compound on cell death due to oxidative stress in KSS patient-derived fibroblasts. When the compound concentration of each compound showing the inhibitory effect on cell death due to oxidative stress in KSS patient-derived fibroblasts is 3 μmol / L, it is expressed as ++, and when it is 10 μmol / L, it is expressed as +. This result shows that these compounds can suppress cell death due to oxidative stress in patients with mitochondrial diseases such as KSS, suggesting that the compounds of the present invention can treat mitochondrial diseases such as KSS.

[Test Example 2: Inhibitory effect on cell death by oxidative stress in LHON patient-derived fibroblasts]
In order to examine the effect of suppressing cell death due to oxidative stress of LHON patient-derived fibroblasts with respect to the compound of the present invention, LHON patient-derived fibroblasts treated with glutathione synthesis inhibitor BSO are cultured in the presence of the compound, Cell viability was measured.

[Method]
1.5 × 10 ⁴ LHON patient-derived fibroblasts per well were seeded in a 48-well cell culture plate and then cultured for 24 hours. A glutathione synthesis inhibitor BSO (manufactured by Sigma-Aldrich) was added at 100 μmol / L. It mixed in the culture solution so that it might become. After culturing for 24 hours in the presence of BSO, each Example compound was mixed in the culture solution to 3 or 10 μmol / L. After culturing for 3 days in the presence of the compound, the number of viable cells was measured using Cell Count Reagent SF (Nacalai Tesque), and the cell viability was calculated. In addition, as a control for the oxidative stress load, a well to which both BSO and the compound were not added was used, and as a control for the effect of the compound, a BSO added well was used.

[result]
Table 7 shows the inhibitory effect of each compound on cell death due to oxidative stress in LHON patient-derived fibroblasts. When the compound concentration at which each compound has an inhibitory effect on cell death due to oxidative stress in LHON patient-derived fibroblasts is 3 μmol / L, it is expressed as ++, and when it is 10 μmol / L, it is expressed as +. This result indicates that these compounds can suppress cell death due to oxidative stress in patients with mitochondrial diseases such as LHON, suggesting that the compounds of the present invention can treat mitochondrial diseases such as LHON.

[Test Example 3: Inhibitory effect on cell death due to oxidative stress in ALS patient-derived fibroblasts]
In order to examine the effect of suppressing cell death due to oxidative stress of ALS patient-derived fibroblasts, ALS patient-derived fibroblasts treated with BSO were cultured in the presence of Example 1 and the cell viability was measured.

[Method]
A 96-well cell culture plate was seeded with 6.4 × 10 ³ ALS patient-derived fibroblasts per well using DMEM medium containing 1% FBS. One day after cell seeding, the glutathione synthesis inhibitor BSO was mixed in the culture solution to 100 μmol / L. After culturing for 1 day in the presence of BSO, the compound of Example 1 was mixed in the culture solution so as to be 1, 3, 10 or 30 μmol / L. After further culturing for 2 days in the presence of the compound, the number of viable cells in each well was measured using Cell Counting Kit-8 (Dojindo Laboratories), and the cell viability was calculated. At this time, a well to which both BSO and the compound were not added was used as a control for oxidative stress load, and a BSO-added well was used as a control for the effect of the compound.

[result]
The compound of Example 1 was statistically detected at 3, 10, and 30 μmol / L in Dunnett's multiple comparison test for cell death induced by 100 μmol / L BSO in the group added with BSO and DMSO. It showed a significant inhibitory effect. From these results, it was suggested that the compound of the present invention may be able to improve the pathology of ALS patients by suppressing the damage to cells caused by oxidative stress.

  In addition to KSS, LHON, and ALS, using fibroblasts derived from patients with other diseases (neurodegenerative diseases, immune neurological diseases, cerebral ischemic diseases, renal diseases, muscle diseases, heart diseases) The inhibitory effect of the compound of the present invention on cell death due to oxidative stress in various fibroblasts can be confirmed by the same or the same method as described above.

  The EC50 value of the cell death inhibitory effect of the compound of the present invention can be calculated using statistical analysis software Stat Preclinica (Takumi Information Technology). Specifically, the EC50 value is obtained by analyzing the data using a technique such as “Dx calculation (logistic curve fitting): response rate input” included in the dose-response data analysis.

  The compound of the present invention exhibits a remarkable cell death inhibitory effect on cell death induced in cells of a patient with a disease associated with abnormal mitochondrial function, and therefore a therapeutic or prophylactic agent for a disease or condition associated with abnormal mitochondrial function Can be provided. More specifically, it is useful as a therapeutic and / or prophylactic agent for mitochondrial diseases, neurodegenerative diseases, immune neurological diseases, cerebral ischemic diseases, renal diseases, muscle diseases, and heart diseases.

Claims (23)

The following formula (I):

[Wherein, X ^a , X ^b , X ^c and X ^d each independently represent a hydrogen atom, a fluorine atom, a chlorine atom, a C _1-4 alkyl group, or a C _1-4 alkoxy group;
A is
(A) The following formula (II):

(Where
(1) 1 to 3 of Y ^a , Y ^b , Y ^c , Y ^d and Y ^e each independently represent a chlorine atom, and the rest each independently represents a hydrogen atom, a fluorine atom, C Represents a _1-4 alkyl group or a C _1-4 alkoxy group;
(2) 1-3 of Y ^a , Y ^b , Y ^c , Y ^d and Y ^e each independently represent a C _1-4 alkyl group, and the rest each independently represents a hydrogen atom, Represents a fluorine atom or a C _1-4 alkoxy group;
(3) 1-3 of Y ^a , Y ^b , Y ^c , Y ^d and Y ^e each independently represent a C _1-4 alkoxy group, and the rest each independently represents a hydrogen atom, Represents a fluorine atom, or (b) a C _4-6 alkyl group substituted with 1 to 5 fluorine atoms,
The following compounds:
4- (4-chlorophenyl) -2- (1H-indol-3-yl) -4-oxobutanoic acid,
6,6,7,7,7-pentafluoro-2- (1H-indol-3-yl) heptanoic acid,
4- (3,4-dichlorophenyl) -2- (1H-indol-3-yl) -4-oxobutanoic acid,
4- (4-chloro-3-methylphenyl) -2- (1H-indol-3-yl) -4-oxobutanoic acid,
2- (1H-indol-3-yl) -4- (4-methylphenyl) -4-oxobutanoic acid,
2- (1H-indol-3-yl) -4-oxo-4- (4-propylphenyl) butanoic acid,
2- (1H-indol-3-yl) -4-oxo-4-[(4-propan-2-yl) phenyl] butanoic acid,
4- (4-tert-butylphenyl) -2- (1H-indol-3-yl) -4-oxobutanoic acid,
4- (2,4-dimethylphenyl) -2- (1H-indol-3-yl) -4-oxobutanoic acid,
4- (3,4-dimethylphenyl) -2- (1H-indol-3-yl) -4-oxobutanoic acid,
4- (2,5-dimethylphenyl) -2- (1H-indol-3-yl) -4-oxobutanoic acid,
2- (1H-indol-3-yl) -4- (4-methoxyphenyl) -4-oxobutanoic acid,
4- (4-ethoxyphenyl) -2- (1H-indol-3-yl) -4-oxobutanoic acid,
4- (4-tert-butylphenyl) -2- (7-ethyl-1H-indol-3-yl) -4-oxobutanoic acid,
4- (4-ethoxyphenyl) -2- (6-methoxy-1H-indol-3-yl) -4-oxobutanoic acid,
Or a pharmaceutically acceptable salt thereof.   The compound according to claim 1, wherein A is a group represented by the formula (II), or a pharmaceutically acceptable salt thereof. 1-3 of Y ^a , Y ^b , Y ^c , Y ^d and Y ^e are each independently a chlorine atom; the rest are each independently a hydrogen atom, a fluorine atom, C _1-4 The compound or pharmaceutically acceptable salt thereof according to claim 1 or 2, which is an alkyl group or a _C1-4 alkoxy group. 1 to 3 of Y ^a , Y ^b , Y ^c , Y ^d and Y ^e are each independently a chlorine atom; the rest are each independently a hydrogen atom, a fluorine atom, or C _1- The compound or a pharmaceutically acceptable salt thereof according to claim 1 or 2, which is a _4- alkyl group. 1 to 3 of Y ^a , Y ^b , Y ^c , Y ^d and Y ^e are each independently a C _1-4 alkyl group; the rest are each independently a hydrogen atom, a fluorine atom or The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, which is a _C1-4 alkoxy group. 1 to 3 of Y ^a , Y ^b , Y ^c , Y ^d and Y ^e are each independently a C _1-4 alkyl group; the rest are each independently a hydrogen atom or a fluorine atom. A compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 6, wherein Y ^c is a chlorine atom or a C _1-4 alkyl group. 1 to 3 of Y ^a , Y ^b , Y ^c , Y ^d and Y ^e are each independently a C _1-4 alkoxy group; the rest are each independently a hydrogen atom or a fluorine atom. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein A is a C _4-6 alkyl group substituted with 1 to 5 fluorine atoms. Among ^{X a,} X b, X ^c and ^{X d,} at least one of a fluorine atom, a chlorine _atom, a _{C 1-4} alkyl group or a _{C 1-4} alkoxy group, any one of the preceding claims Or a pharmaceutically acceptable salt thereof. The compound according to claim 1 or a pharmaceutically acceptable salt thereof selected from the following compounds:
4- (2,4-dichlorophenyl) -2- (1H-indol-3-yl) -4-oxobutanoic acid,
4- (3-chlorophenyl) -2- (1H-indol-3-yl) -4-oxobutanoic acid,
4- (2,4-dichlorophenyl) -2- (5-fluoro-1H-indol-3-yl) -4-oxobutanoic acid,
4- (2,4-dichlorophenyl) -2- (6-fluoro-1H-indol-3-yl) -4-oxobutanoic acid,
2- (5-chloro-1H-indol-3-yl) -4- (2,4-dichlorophenyl) -4-oxobutanoic acid,
2- (6-chloro-1H-indol-3-yl) -4- (2,4-dichlorophenyl) -4-oxobutanoic acid,
4- (2,4-dichlorophenyl) -2- (5-methyl-1H-indol-3-yl) -4-oxobutanoic acid,
4- (2,4-dichlorophenyl) -2- (5-ethyl-1H-indol-3-yl) -4-oxobutanoic acid,
4- (2,4-dichlorophenyl) -2- (5-methoxy-1H-indol-3-yl) -4-oxobutanoic acid,
4- (2,4-dichlorophenyl) -2- (6-methoxy-1H-indol-3-yl) -4-oxobutanoic acid,
4- (3-tert-butylphenyl) -2- (1H-indol-3-yl) -4-oxobutanoic acid,
4- (4-tert-butylphenyl) -2- (5-fluoro-1H-indol-3-yl) -4-oxobutanoic acid,
4- (4-tert-butylphenyl) -2- (5-chloro-1H-indol-3-yl) -4-oxobutanoic acid,
4- (4-tert-butylphenyl) -2- (5-methyl-1H-indol-3-yl) -4-oxobutanoic acid,
4- (4-tert-butylphenyl) -2- (5-methoxy-1H-indol-3-yl) -4-oxobutanoic acid,
4- (4-tert-butylphenyl) -2- (6-methoxy-1H-indol-3-yl) -4-oxobutanoic acid,
4- (2-chlorophenyl) -2- (1H-indol-3-yl) -4-oxobutanoic acid,
8,8,8-trifluoro-2- (1H-indol-3-yl) octanoic acid. A compound or a pharmaceutically acceptable salt thereof selected from the following:
4- (3,4-difluorophenyl) -2- (1H-indol-3-yl) -4-oxobutanoic acid,
4- (2,4-difluorophenyl) -2- (7-methyl-1H-indol-3-yl) -4-oxobutanoic acid,
4- (2,4-difluorophenyl) -4-oxo-2- [6- (propan-2-yl) -1H-indol-3-yl] butanoic acid,
4- (2,4-difluorophenyl) -2- (5-ethyl-1H-indol-3-yl) -4-oxobutanoic acid,
2- (6-chloro-1H-indol-3-yl) -4- (2,4-difluorophenyl) -4-oxobutanoic acid,
4- (3,5-difluorophenyl) -2- (1H-indol-3-yl) -4-oxobutanoic acid,
4- (2,4-difluorophenyl) -2- (4-methyl-1H-indol-3-yl) -4-oxobutanoic acid,
4- (2,4-difluorophenyl) -2- (6-methyl-1H-indol-3-yl) -4-oxobutanoic acid,
4- (2,4-difluorophenyl) -2- (7-ethyl-1H-indol-3-yl) -4-oxobutanoic acid,
4- (2,4-difluorophenyl) -2- (4-methoxy-1H-indol-3-yl) -4-oxobutanoic acid,
4- (2,5-difluorophenyl) -2- (1H-indol-3-yl) -4-oxobutanoic acid,
4- (2,3-difluorophenyl) -2- (1H-indol-3-yl) -4-oxobutanoic acid.   The pharmaceutical which contains the compound as described in any one of Claims 1-12, or its pharmaceutically acceptable salt as an active ingredient.   The therapeutic agent of the disease resulting from a mitochondrial dysfunction containing the compound or its pharmaceutically acceptable salt as described in any one of Claims 1-12 as an active ingredient. Formula (I) below

[Wherein, X ^a , X ^b , X ^c and X ^d each independently represent a hydrogen atom, a fluorine atom, a chlorine atom, a C _1-4 alkyl group, or a C _1-4 alkoxy group;
A is
(A) The following formula (II):

(Where
(1) 1 to 3 of Y ^a , Y ^b , Y ^c , Y ^d and Y ^e each independently represent a chlorine atom, and the rest each independently represents a hydrogen atom, a fluorine atom, C Represents a _1-4 alkyl group or a C _1-4 alkoxy group;
(2) 1-3 of Y ^a , Y ^b , Y ^c , Y ^d and Y ^e each independently represent a C _1-4 alkyl group, and the rest each independently represents a hydrogen atom, Represents a fluorine atom or a C _1-4 alkoxy group;
(3) 1-3 of Y ^a , Y ^b , Y ^c , Y ^d and Y ^e each independently represent a C _1-4 alkoxy group, and the rest each independently represents a hydrogen atom, Represents a fluorine atom, or (b) a C _4-6 alkyl group substituted with 1 to 5 fluorine atoms,
4- (4-Chlorophenyl) -2- (1H-indol-3-yl) -4-oxobutanoic acid and 6,6,7,7,7-pentafluoro-2- (1H-indole-3) A therapeutic agent for diseases caused by mitochondrial dysfunction, which comprises, as an active ingredient, a compound represented by -yl) excluding heptanoic acid or a pharmaceutically acceptable salt thereof.   The therapeutic agent according to claim 14 or 15, wherein the disease caused by mitochondrial dysfunction is mitochondrial disease, neurodegenerative disease, immune neurological disease, cerebral ischemic disease, renal disease, muscle disease, or heart disease.   Mitochondrial diseases include Leigh's encephalopathy, stroke-like seizure syndrome (MELAS), chronic progressive extraocular palsy syndrome (CPEO), Kearns-Sayer syndrome (KSS), myoclonic epilepsy syndrome with red rag fibers (MERRF), Pearson's disease, The therapeutic agent according to claim 16, which is Leber hereditary optic neuropathy (LHON), mitochondrial encephalomyopathy, Bath syndrome, or lactic acidosis.   Neurodegenerative diseases include amyotrophic lateral sclerosis (ALS), Parkinson's disease, Alzheimer's disease, Huntington's disease, Friedreich's ataxia, multiple system atrophy, progressive supranuclear palsy, spinocerebellar degeneration, spinal muscular The therapeutic agent according to claim 16, which is atrophy, bulbospinal muscular atrophy, or Charcot-Marie-Tooth disease.   The therapeutic agent according to claim 16, wherein the immune neurological disease is Guillain-Barre syndrome, multiple sclerosis, Fischer syndrome, chronic inflammatory demyelinating polyneuritis, or myasthenia gravis.   The therapeutic agent according to claim 16, wherein the cerebral ischemic disease is cerebral infarction.   Kidney disease is renal failure, amyloid kidney, membranous nephropathy, focal glomerulosclerosis, IgA nephropathy, acute tubular necrosis, nephrotic syndrome, diabetic nephropathy, gout kidney, renal edema, renal tumor, kidney The therapeutic agent according to claim 16, which is ischemic injury, renal ischemia reperfusion injury, or cystic kidney.   The muscular disease is progressive muscular dystrophy, myotonic dystrophy, congenital myopathy, metabolic myopathy, distal myopathy, inflammatory myopathy, age-related muscle atrophy (sarcopenia), or disuse muscle atrophy 16. The therapeutic agent according to 16.   The therapeutic agent according to claim 16, wherein the heart disease is myocardial infarction, heart failure, ischemic heart disease, or cardiomyopathy.